Smooth muscle cells are thought to be the major site of injury in chronic vascular diseases including atheroma and chronic progressive glomerular diseases. We initially found that heparin decreased mesangial cell- the smooth muscle cell in the glomerulus- proliferation and extracellular matrix production in a dose-dependent manner. Furthermore non-anticoagulant heparin decreased lesions in the glomeruli of mice transgenic for GH which have a very severe form of glomerulosclerosis. This led us to test heparin analogues in several forms of progressive vascular diseases. The availability of an oral compound pentosan polysulfate which shares some properties with heparin led us to propose this drug in the treatment of vascular diseases. A CRADA was developed and signed with Baker-Norton company in order to investigate the possible therapeutic applications of this drug in chronic small blood vessel (glomerulosclerosis) and large blood vessel (atherosclerosis)diseases in experimental animals and, eventually, in man. Studies in glomerulosclerosis initially focused on bGH mice, since these mice develop uremic glomerular disease. The drug was administered in the drinking water for 6 weeks after they already had severe established lesions. Following treatment we observed a significant decrease in the amount of mesangial matrix and a decrease in the expression of genes coding for basement membrane and interstitial collagens. Similar experiments were done with diabetic mice, with and without a genetic predisposition to glomerulosclerosis. A sharp improvement was observed in sclerosis-prone diabetic mice irrespective of the glycemic level. Of course, no lesions were present in sclerosis-resistant mice. Atherosclerosis was evaluated in cholesterol-fed Watanabe rabbits, animals which have a genetic defect in the LDL receptor. Animals fed with tap water developed severe aortic atherosclerosis, whereas animals fed pentosan polysulfate in the drinking water had a 50% reduction in lesions, on average.